The goal of this project is to examine frontal lobe cortical and white matter structures in individuals at high risk for having Chronic Traumatic Encephalopathy (CTE) using in vivo neuroimaging techniques. The proposed study will also examine the association between structural changes in the frontal lobe and specific brain trauma exposure factors which may serve as potential risk factors for this neurodegenerative disease. CTE is a preventable cause of dementia and is thought to be caused, in part, by repetitive concussive and/or subconcussive brain trauma. However, repetitive brain trauma alone is not sufficient to cause the disease, and additional risk factors are not yet known. At thi time CTE can only be diagnosed postmortem, and all current knowledge of CTE has been derived from postmortem neuropathological analysis of brains and spinal cords and retrospective interviews with family members or others close to the donor. Neuropathological analysis has demonstrated that CTE is a unique tauopathy distinct from other neurodegenerative diseases such as Alzheimer's disease and Frontotemporal Dementia (FTD). Many of the symptoms associated with CTE, including executive dysfunction, lack of impulse control, and working memory impairment, are associated with dysfunction of the prefrontal cortex and frontal white matter pathways. The proposed study will include a sample of participants who are at high risk for CTE and a control group with no previous exposure to brain trauma. The high-risk group will include 100 former NFL players, ages 40-69, with a history of high exposure to brain trauma based on the position played and total number of years of football played across all levels. The control group will include age-matched males with a history of participation in non-contact organized sports and no history of exposure to concussive or subconcussive brain trauma. Structural neuroimaging will be used to examine the volumes of the dorsolateral prefrontal and orbitofrontal cortices. In addition, diffusion tensor imaging will e used to examine the uncinate fasciculus, a white matter tract connecting the prefrontal cortex and temporal lobe, and the genu of the corpus callosum, a white matter pathway connecting the right and left prefrontal cortices. In addition, the neuroimaging results in the high-risk group wil be compared to specific brain trauma exposure factors, including the age of first exposure to brain trauma through participation in football and total years of participation in football across ll levels, to examine the relationship between these risk factors and the severity of frontal lobe degeneration. Results of this investigation will provide important knowledge of in vivo frontal lobe structural changes in CTE. Given the millions of Americans involved in contact sports across all levels as well as military personnel who have experienced repetitive brain trauma from blast injuries, an improved understanding of frontal lobe dysfunction in CTE and other factors that influence the progression of CTE will likely have a significant impact on public health. PUBLIC HEALTH RELEVANCE: Chronic Traumatic Encephalopathy (CTE) is a degenerative disease of the brain that occurs as a result of repetitive brain trauma, such as that received by athletes involved in football and other contact sports. Millions of Americans participate in contac sports at all levels; thus, it is critical to be able to detect, diagnose, treat, and take steps to prevent this progressive brain disease. This study is part of a larger study, which is the first to address these issues and, therefore, may have a considerable impact on public health.